Project Summary The brain is often bombarded by streams of information from multiple sources simultaneously. In real world situations, rapidly changing contexts can shift the meaning of a sensory stimulus, requiring an animal to change its response to a given stimulus on the fly. The ability to flexibly and appropriately adjust behavioral responses in changing contexts is critical not only for survival, but also to thrive in society. Indeed, disruptions in this ability characterize many brain disorders. The goal of our lab is to understand the mechanisms that underlie the flexibility of information processing in cortical circuits, focusing on how inhibitory neurons gate the flow of information between sensory and association regions in a context-dependent manner. Head-fixed mice voluntarily running on a spherical treadmill will be rapidly shifted between behavioral contexts within single sessions. These contexts will include spontaneous (no experimenter-controlled sensory stimulation), passive delivery of visual and auditory stimuli, and active performance of auditory perceptual tasks in virtual reality. In each of these contexts, two-photon imaging of calcium activity will be used to monitor the responses of hundreds of genetically labeled inhibitory and excitatory neurons simultaneously. In some experiments, optogenetics will be used to activate specific incoming projections to the imaged region, or to inactivate specific cell types. These tools will be combined in three main projects. In the first project, the inhibitory mechanisms gating the flow of information between cortical regions will be dissected, to determine whether canonical rules define inhibitory operations across cortex, or if local specializations allow greater flexibility at different hierarchical levels of the cerebral cortex. In the second project, the roles of inhibitory neurons in setting network dynamics will be determined, and the consequences of shifting network dynamics on signal processing will be defined. In the third project, neuromodulatory recruitment of inhibitory circuits across the cortical hierarchy will be described, to determine how shifts in brain state affect information processing. To understand the neural underpinnings of perception, attention, and behavioral flexibility, it is critical to study the interaction between brain areas, rather than to focus on single brain regions in isolation. The experiments proposed here will use new tools to answer fundamental questions about how local circuits interact to process information, toward the goal of understanding how the distributed cortical network gives rise to cognitive processes such as attention and perception. !